NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

Nivedita M. Ratnam, Jennifer M. Peterson, Erin E. Talbert, Katherine J. Ladner, Priyani V. Rajasekera, Carl R. Schmidt, Mary E. Dillhoff, Benjamin J. Swanson, Ericka Haverick, Raleigh D. Kladney, Terence M. Williams, Gustavo W. Leone, David J. Wang, Denis C. Guttridge

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

Original languageEnglish (US)
Pages (from-to)3796-3809
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number10
DOIs
StatePublished - Oct 2 2017

ASJC Scopus subject areas

  • Medicine(all)

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    Ratnam, N. M., Peterson, J. M., Talbert, E. E., Ladner, K. J., Rajasekera, P. V., Schmidt, C. R., Dillhoff, M. E., Swanson, B. J., Haverick, E., Kladney, R. D., Williams, T. M., Leone, G. W., Wang, D. J., & Guttridge, D. C. (2017). NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. Journal of Clinical Investigation, 127(10), 3796-3809. https://doi.org/10.1172/JCI91561